Diagnostic significance of determining the level of extracellular fetal DNA in pregnant women with preeclampsia and fetal growth restriction
Objective. To evaluate the diagnostic significance of determining extracellular fetal DNA in the plasma of pregnant women with preeclampsia and fetal growth restriction.Sadekova A.A., Khachatryan Z.V., Krasnyi A.M., Kan N.E., Khachaturyan A.A., Tyutyunnik V.L.
Subjects and methods. Plasma samples from 55 women were investigated during the study. The pregnant women were divided into groups: 1) 17 pregnant women with preeclampsia and fetal growth restriction; 2) 19 patients with a confirmed diagnosis of preeclampsia without fetal growth restriction; 3) 19 women with physiological pregnancy. Quantitative PCR analysis was used in all the patients to measure the plasma level of extracellular fetal DNA, by determining the concentration of the hypermethylated RASSF1A gene.
Results. The pregnant women with preeclampsia and growth restriction were found to have a significantly higher level of extracellular fetal DNA (284 GE/ml for impaired fetoplacental blood flow by Doppler ultrasound; 339 GE/ml for the absence of impaired fetoplacental blood flow) than those with preeclampsia (79 GE/ml) and apparently healthy pregnant women (25 GE/ml). The level of extracellular fetal DNA in pregnant women with preeclampsia and fetal growth restriction without impaired fetoplacental blood flow was shown to be an indicator of fetal growth restriction at a threshold of 201 GE/ml with a sensitivity of 80% and a specificity of 89%.
Conclusion. The findings indicate that quantitative determination of the plasma level of extracellular fetal DNA can be used to identify groups at risk for fetal growth restriction in pregnant women with preeclampsia. Quantification of the level of extracellular fetal DNA in combination with other methods for fetal assessment can assist in choosing the optimal timing and methods of delivery to improve perinatal outcomes.
Keywords
extracellular fetal DNA
fetal growth restriction
preeclampsia
RASSF1
References
- Макаров И.О., Юдина Е.В., Боровкова Е.И. Задержка роста плода. Врачебная тактика: Учебн. пособие / 3-е изд. М.: МЕДпреcс-информ, 2016; 56 с. [Makarov I.O., Yudina E.V., Borovkova E.I. Fetal growth restriction. Management. Training manual. Medpress-inform. 2016; 56 p. (In Russ.)].
- Gardosi J., Madurasinghe V., Williams M., Malik A., Francis A. Maternal and fetal risk factors for stillbirth: population based study 2013; BMJ 346 (7893): 15.
- Alberry M., Maddocks D., Jones M., Abdel Hadi M., Abdel-Fattah S., Avent N., Soothill P.W. Free fetal DNA in maternal plasma in anembryonic pregnancies: confirmation that the origin is the trophoblast. Prenat Diagn 2007; 27: 415-418.
- Burton G.J., Jauniaux E. Pathophysiology of placental-derived fetal growth restriction. Am J Obstet Gynecol 2018 Feb; 218(2S): S745-S761.
- Kwiatkowski S., Dołegowska B., Kwiatkowska E., Rzepka R., Marczuk N., Loj B., Torbè A. Maternal endothelial damage as a disorder shared by early preeclampsia, late preeclampsia and intrauterine growth restriction. J Perinat Med. 2017 Oct 26; 45 (7): 793-802.
- Colin P. Sibley. Treating the dysfunctional placenta, J Endocrinol. 2017 Aug; 234 (2): R81–R97.
- Dugoff L., Lynch A.M., Cioffi-Ragan D., Hobbins J.C., Schultz L.K., Malone F.D., D’Alton M.E.; FASTER Trial Research Consortium. First trimester uterine artery Doppler abnormalities predict subsequent intrauterine growth restriction. Am J Obstet Gynecol. 2005 Sep; 193 (3 Pt 2): 1208-12.
- Albaiges G., Missfelder-Lobos H., Lees C., Parra M., Nicolaides K.H. One-stage screening for pregnancy complications by color Doppler assessment of the uterine arteries at 23 weeks’ gestation. Obstet Gynecol 2000 Oct; 96 (4): 559-64.
- Yamamoto R., Ishii K., Nakajima E., Sasahara J., Mitsuda. Ultrasonographic prediction of antepartum deterioration of growth-restricted fetuses after late preterm. J Obstet Gynaecol Res. 2018 Jun; 44 (6): 1057-62.
- Berkley E., Chauhan S.P., Abuhamad A. Doppler assessment of the fetus with intrauterine growth restriction. Society for Maternal-Fetal Medicine Publications Committee. Am J Obstet Gynecol. 2012 Apr; 206 (4): 300-8.
- Figueras F., Gardosi J. Intrauterine growth restriction: new concepts in antenatal surveillance, diagnosis, and management. Am J Obstet Gynecol 2011 Apr; 204 (4): 288-300.
- Resnik R. Fetal growth restriction: evaluation and management. www.uptodate.com 2012.
- Figueras F., Gratacós E. Update on the Diagnosis and Classification of Fetal Growth Restriction and Proposal of a Stage-Based Management Protocol. Fetal Diagn Ther 2014; 36: 86-98
- Imdad A., Bautista R.M., Senen K.A., Uy M.E., Mantaring J.B. 3rd, Bhutta Z.A. Umbilical cord antiseptics for preventing sepsis and death among newborns. Cochrane Database Syst Rev. 2013 May 31; (5): CD008635
- Cruz-Martinez R., Figueras F., Hernandez-Andrade E., Puerto B., Gratacós E. Longitudinal brain perfusion changes in near term small for gestational age fetuses as measured by spectra Doppler-indices or by fractional moving blood volume. Am J Obstet Gynecol 2010; 203: 42.el-6.
- Unterscheider J., Daly S., Geary M.P., Kennelly M.M., McAuliffe F.M., O’Donoghue K., Hunter A., Morrison J.J., Burke G., Dicker P., Tully E.C., Malone F.D. Optimizing the definition of intrauterine growth restriction: the multicenter prospective PORTO Study. Am J Obstet Gynecol. 2013 Apr; 208 (4): 290.e1-6.
- Salvianti F., Inversetti A., Smid M., Valsecchi L., Candiani M., Pazzagli M., Cremonesi L., Ferrari M., Pinzani P., Galbiati S. Prospective evaluation of RASSF1A cell-free DNA as a biomarker of pre-eclampsia. Placenta 2015; Sep; 36 (9): 996-1001.
- Papantoniou N., Bagiokos V., Agiannitopoulos K., Kolialexi A., Destouni A., Tounta G., Kanavakis E., Antsaklis A., Mavrou A. RASSF1A in maternal plasma as a molecular marker of preeclampsia. Prenat Diagn. 2013 Jul; 33 (7): 682-7.
- Красный А.М., Грачева М.И., Садекова А.А., Вторушина В.В., Балашов И.С., Кан Н.Е., Боровиков П.И., Кречетова Л.В., Тютюнник В.Л. Комбинированное исследование общей, фетальной ДНК, цитокинов в плазме крови матери при преэклампсии. Бюллетень экспериментальной биологии и медицины 2018; 12: 686-91 [Krasnyi A.M., Gracheva M.I., Sadekova A.A., Vtorushina V.V., Balashov I.S., Kan N.E., Borovikov P.I., Krechetova L.V., Tyutyunnik V.L. Combined study of total, fetal cell-free DNA, cytokines in pregnant women with preeclampsia. Bulletin of Experimental biology and medicine 2018; 12: 686-91. (In Russ.)].
- Jorgez C.J., Bischoff F.Z. Improving Enrichment of Circulating Fetal DNA for Genetic Testing: Size Fractionation Followed by Whole Gene Amplification. Fetal Diagn Ther. 2009 Sep; 25 (3): 31-319
- White H.E., Dent C.L., Hall V.J., Crolla J.A., Chitty L.S. Evaluation of a Novel Assay for Detection of the Fetal Marker RASSF1A: Facilitating Improved Diagnostic Reliability of Noninvasive Prenatal Diagnosis. PLoS One 2012; 7 (9): e45073.
- Fenton T.R, Kim J.H. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatrics 2013; 13 (1): 59.
- Карапетян А.О., Красный А.М., Садекова А.А., Хлестова Г.В., Балашов И.С., Баев О.Р. Изменение концентрации внеклеточной ДНК во время беременности. Акушерство и гинекология 2018; 3: 44-50. [Karapetyan A.O., Krasnyi A.M., Sadekova A.A., Khlestova G.V., Balashov I.S., Baev O.R. A change in the concentration of extracellular DNA during pregnancy. Obstetrics and gynecology 2018; 3: 44-50 (In Russian)].
- Alberry MS, Maddocks DG, Hadi MA, Metawi H, Hunt LP, Abdel-Fattah SA, Avent ND, Soothill PW. Quantification of cell free fetal DNA in maternal plasma in normal pregnancies and in pregnancies with placental dysfunction. Am J Obstet Gynecol. 2009 Jan;200(1):98.e1-6.
- Litwińska E, Litwińska M, Oszukowski P, Szaflik K, Kaczmarek P. Combined screening for early and late pre-eclampsia and intrauterine growth restriction by maternal history, uterine artery Doppler, mean arterial pressure and biochemical markers. Adv Clin Exp Med. 2017 May-Jun; 26 (3):439-448.
- Muñoz-Hernández R, Medrano-Campillo P, Miranda ML, Macher HC, Praena-Fernández JM, Vallejo-Vaz AJ, Dominguez-Simeon MJ, Moreno-Luna R, Stiefel P. Total and Fetal Circulating Cell-Free DNA, Angiogenic, and Antiangiogenic Factors in Preeclampsia and HELLP Syndrome. Am J Hypertens. 2017 Jul 1;30(7):673-682.
- Smid M, Galbiati S, Lojacono A, Valsecchi L, Platto C, Cavoretto P, Calza S, Ferrari A, Ferrari M, Cremonesi L. Correlation of fetal DNA levels in maternal plasma with Doppler status in pathological pregnancies. Prenat Diagn 2006; 26: 785-790.
- Al Nakib M, Desbrière R, Bonello N, Bretelle F, Boubli L, Gabert J, Levy-Mozziconacci A. Total and fetal cell-free DNA analysis in maternal blood as markers of placental insufficiency in intrauterine growth restriction. Fetal Diagn Ther. 2009; 26 (1): 24-8.
- Stein W, Müller S, Gutensohn K, Emons G, Legler T. Cell-free fetal DNA and adverse outcome in low risk pregnancies. Eur J Obstet Gynecol Reprod Biol. 2013 Jan; 166 (1): 10-3.
- Poon LC, Musci T, Song K, Syngelaki A, Nicolaides KH. Maternal plasma cell-free fetal and maternal DNA at 11-13 weeks’ gestation: relation to fetal and maternal characteristics and pregnancy outcomes. Fetal Diagn Ther. 2013; 33 (4): 215-23.
- Koide K, Sekizawa A, Iwasaki M, Matsuoka R, Honma S, Farina A, Saito H, Okai T. Fragmentation of cell-free fetal DNA in plasma and urine of pregnant women. Prenat Diagn. 2005 Jul; 25 (7): 604-7.
Received 09.11.2018
Accepted 07.12.2018
About the Authors
Sadekova Alsu A., scientific researcher of the cytology laboratory of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov Ministry of Health of Russia. Tel.: +7(495)438-22-72. E-mail: a_sadekova@oparina4.ru 117997, Moscow, Ac. Oparina, 4 str.Khachatryan Zarine V., postgraduate student of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov Ministry of Health of Russia. Tel.: +7(909)656-24-56. E-mail: z.v.khachatryan@gmail.com 117997, Moscow, Ac. Oparina, 4 str..
Krasnyi Aleksey M., PhD, the head of the cytology laboratory of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov Ministry of Health of Russia., senior scientist, laboratory of evolutionary developmental biology, N.K. Koltzov Institute of Developmental Biology of Russian Academy of Sciences Tel.: +7(495)438-22-72. E-mail: alexred@list.ru 117997, Moscow, Ac. Oparina, 4 str. 119334, Moscow, Vavilova str. 26, Russia.
Kan Natalia E., PhD, MD, the head of the obstetric department of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov Ministry of Health of Russia. Tel.: +7-926-220-86-55. E-mail: kan-med@mail.ru. Number Researcher ID B-2370-2015.
ORCID ID 0000-0001-5087-5946 117997, Moscow, Ac. Oparina, 4 str.
Khachaturyan Anuta A., postgraduate student of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov Ministry of Health of Russia. Tel.: +7(926)845-39-53. E-mail: x.anyt37@mail.ru 117997, Moscow, Ac. Oparina, 4 str.
Tyutyunnik Victor L., PhD, MD, the head of the obstetric physiological department of the National Medical Research Center for Obstetrics, Gynecology and Perinatology named after Academician V.I. Kulakov Ministry of Health of Russia. Tel.: +7(903)969-50-41. E-mail: tioutiounnik@mail.ru. Number Researcher ID B-2364-2015.ORCID ID 0000-0002-5830-5099 117997, Moscow, Ac. Oparina, 4 str.
For citations: Sadekova A.A., Khachatryan Z.V., Krasnyi A.M.,Kan N.E., Khachaturyan A.A., Tyutyunnik V.L. Diagnostic significance of determining the level of extracellular fetal dna in pregnant women with preeclampsia and fetal growth restriction/ andintrauterine growth restriction.
Akusherstvo i Ginekologiya / Obstetrics and Gynecology. 2019; (8): 144-49 (in Russian)
http://dx.doi.org/10.18565/aig.2019.8.144-149
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